Proliferation and differentiation of cells of multicellular organisms are controlled by hormones and polypeptide growth factors. These diffusable molecules allow cells to communicate with each other and act in concert to regulate cell proliferation and organ development; and regulate repair and regeneration of damaged tissue. Hormones and growth factors influence cellular metabolism by binding to receptors. Receptors may be integral membrane proteins that are linked to signaling pathways within the cell. Other classes of receptors are soluble molecules, such as transcription factors. Hormonal effects, including hormone and soluble receptor interaction, are essential for effective thyroid function.
The thyroid gland is a major endocrine gland during normal human growth and development. In adults, the major role of the thyroid is to maintain metabolic stability, primarily through thyroid hormone production and regulation. Virtually every organ in the body is affected by thyroid hormones. Thus, thyroid malfunction is associated with several disease states. Thyroid diseases are relatively common, occurring in the form of thyroid gland size and shape abnormalities (goiter) and abnormalities in thyroid hormone secretion. Thyroid malfunction may also result from non-thyroidal illnesses or nutrient deficiencies that alter thyroid physiology. Examples of common thyroid diseases are thyrotoxicosis, hypothyroidism, Grave's disease, hyperthyroidism and thyroid tumors. For general review see, Felig, P, Baxter, J. D. and Frohman, L. A. (eds.), Endocrinology and Metabolism, McGraw Hill, NY, 3rd ed., 1995, pp. 432-553; and Bennett, J. C. and Plum, F. (eds.), Textbook of Medicine, W. B. Saunders Co., Philadelphia, 20th ed., 1996, pp. 1227-1245.
The most extensively studied thyroid hormones are thyroxine (T4), triiodothyronine (T3) and thyroid stimulating hormone (TSH). T4 is produced exclusively in the thyroid, whereas T3 is produced both by the thyroid and by extra-thyroidal enzymatic 5'-deiodination of T4. Both T3 and T4 are secreted and are derived from enzymatic cleavage of thyroglobulin; thyroglobulin, a major thyroid protein, is the intracellular storage form of T4 and T3. Both the biosynthesis and secretion of T4 and T3 are stimulated by pituitary TSH; which, in turn, is inhibited by circulating T3 and T4 and stimulated by hypothalamic thyrotropin-releasing hormone (TRH).
T3 functions as a ligand for thyroid hormone nuclear receptors, which mediate all known physiologic actions of thyroid hormone. These receptors are members of the steroid nuclear receptor superfamily; they bind DNA and activate mRNA transcription. The thyroid receptor has different activities when bound or not bound by its acidic T3 ligand. In circulation, T4 and T3 are bound by several different serum proteins until they reach their sites of action in various organs and tissues.
Thyroid hormones modulate a wide number of metabolic processes by regulating the production and activity of various enzymes, the production and metabolism of other hormones, and utilization of substrates, vitamins, and minerals. Not all of these effects are due to T3 transcriptional regulation. For example, non-nuclear actions include amino acid and sugar transport stimulation in lymphoid cells, calcium-ATPase activity in red blood cells and heart cells, and other membrane interactions. For review of the metabolic effect and diseases of thyroid hormones, see Braverman, L. E. (ed.), Diseases of the Thyroid, Humana Press, Totowa, N.J., 1997. Other known effectors contribute to this complex physiologic scheme. Currently unknown effectors are probably important as well.
There remains a need in the art to further elucidate thyroid-related physiology and to provide additional regulatory molecules. Of particular interest are regulatory proteins, including additional thyroid hormones, that influence thyroid function or are secreted from thyroid with extrathymic effects. Such hormones would be useful for, inter alia, restoring normal thyroid function in patients suffering various thyroid ailments and as targets for the development of small-molecule drugs. The demonstrated in vivo activities of known thyroid hormones illustrates the enormous clinical potential of, and need for, other thyroid hormones, their agonists and antagonists. The present invention provides such polypeptides for these and other uses that should be apparent to those skilled in the art from the teachings herein.